Composition for contraception

ABSTRACT

A combination product for oral contraception is disclosed comprising an estrogen selected from
         2.0 to 6.0 mg of 17β-estradiol and   0.020 mg of ethinylestradiol;
 
and a gestagen selected from
   0.25 to 0.30 mg of drospirenone and   0.1 to 0.2 mg of cyproterone acetate,
 
followed by 5 or 4 pill-free or sugar pill days.

ThisNotice: More than one reissue application has been filed for thereissue of U.S. Pat. No. 5,824,667: this Ser. No. 11/892,969continuation reissue application is a divisional of reissue applicationSer. No. 10/916,600 of Aug. 12, 2004 now abandoned, which is acontinuation of reissue application Ser. No. 10/193,758 filed Jul. 12,2002, now abandoned, which is a continuation of reissue application Ser.No. 09/504,084, filed Feb. 15, 2000, now U.S. Pat. No. Re. 37,838, whichis a reissue of application Ser. No. 08/742,147, filed Oct. 31, 1996,now U.S. Pat. No. 5,824,667, which is a continuation of the applicationSer. No. 08/268,996 filed Jun. 30, 1994, now U.S. Pat. No. 5,583,129;and reissue application Ser. No. 10/080,617, filed on Feb. 25, 2002, nowU.S. Pat. No. Re. 38,253, is a continuation of reissue application Ser.No. 09/503,952, now U.S. Pat. No. Re. 37,564, which also is a reissue ofapplication Ser. No. 08/742,147, filed Oct. 31, 1996, now U.S. Pat. No.5,824,667, which is a continuation of the application Ser. No.08/268,996, filed Jun. 30, 1994, now U.S. Pat. No. 5,583,129; and acontinuation reissue application of Ser. No. 10/916,600 has been filed,on Mar. 24, 2006, having Ser. No. 11/388,172.

DESCRIPTION

This invention relates to the common use of estrogens and gestagens forthe production of a combination preparation for oral contraception and acorresponding pack containing this combination preparation.

Combination preparations for oral contraception are already known, forexample, Femovan® [DE-PS 2 546 062] or Marvelon® [DE-OS 2 361 120].These preparations consist of 21 active ingredient-containing(estrogen/gestagen) dosage units and 7 active ingredient-free coatedtablets (sugar pills; placebos). The dose to be administered daily isuniformly high in each case (so-called single-phase preparations) andproduces the desired contraceptive effect in the entire intake periodand in the intake pause or during the intake of the placebos. In mostpreparations, a 7-day interruption of the intake of activeingredient-containing dosage units was considered necessary until quiterecently to trigger a reliable withdrawal bleeding and thus to achieve asatisfactory cycle control.

Other preparations, which exhibit more than 21 dosage units containingan estrogenic and progestational active ingredient, and in which theintake pause is partially (Ijzerman, Pasquale) or completely (Kuhl)bridged over by estrogen-containing dosage units. In this case, it ispossible that the synthetic estrogen ethinylestradiol otherwisecontained in oral contraceptives is replaced partially or completely bya conjugated estrogen, preferably estradiol.

A combination preparation for substitution therapy and contraception forfemales before menopause (approximately starting from the 40th year oflife) is known from EP-A-0 253 607. This combination preparationcontains an estrogen from the group

-   -   17β-Estradiol,    -   ethinylestradiol and    -   mestranol        as well as a gestagen from the group    -   levonorgestrel,    -   gestodene,    -   desogestrel,    -   3-ketodesogestrel and    -   norethindrone.

A thus selected composition is to offset hormonal irregularities in thetransition phase of premenopause and to help alleviate the symptomscaused by the hormonal changeover of the female organism in this phase.Such a composition simultaneously assures a premenopausal female thecontraceptive protection still necessary at this age.

The development of new oral contraceptives for females of reproductiveage before premenopause was characterized during the last twenty yearsabove all by the reduction of the estrogen and gestagen dosages.

The reduction of the daily hormone dose was connected with theexpectation to minimize the frequency of undesired side effects.Epidemiological data collected in the meantime confirm the desired trendtoward better compatibility of lower-dosed preparations relative tocardiovascular complications [(1.) Thorogood, M., Oral Contraceptivesand Cardiovascular Disease: An Epidemiologic Overview;Pharmacoepidemiology and Drug Safety, Vol. 2: 3-16 (1993); (2.)Gerstman, B. B.; Piper, J. M.; Tomita, D. K.; Ferguson, W. J.; Stadel,B. V.; Lundin, F. E.; Oral Contraceptive Estrogen Dose and the Risk ofDeep Venous Thromboembolic Disease, Am. J. E., Vol. 133, No. 1, 32-36(1991); (3.) Lidegaard, O., Oral contraception and risk of a cerebralthromboembolic attack: results of a case-control study; BMJ Vol. 306,956-63 (1993); (4.) Vessey, M.; Mant, D.; Smith, A.; Yeates, D.; Oralcontraceptives and venous thromboembolism: findings in a largeprospective study; BMJ, Vol. 292, (1986); (5.) Mishell, D. R., OralContraception: Past, Present and Future Perspectives; Int. J. Fertil.,36 Suppl., 7-18 (1991)].

It is assumed that a correlation exists above all between the level ofthe estrogen dose and the incidence of cardiovascular diseases. But themaintenance of the contraceptive effectiveness stands in the way of anextreme reduction of the daily estrogen dose. Although theovulation-inhibiting effect of the low-dosed oral contraceptives iscaused mainly by the gestagenic component, the estrogenic component alsomakes a significant contribution to the central inhibition action and tothe ovarian suppression (ovulation inhibition). Moreover, the dailyestrogen dose must not fall below the minimum dose ranges, so that asatisfactory cycle control can be assured (Der Frauenarzt [TheGynecologist]; 34, 7: 793 (1993)].

The lowest estrogen dose contained in an oral contraceptive on themarket at this time is 20 μg of ethinylestradiol, combined with 150 μgof desogestrel (Mercilon). Although the cycle control of thispreparation is, as expected, somewhat poorer in comparison topreparations with a higher estrogen dose, the high acceptance rate ofMercilon indicates a small clinical relevance of this drawback. But theobservation, made identically in several studies, of a lesser ovarialsuppression of the preparation containing 20 μg of ethinylestradiolrepresents a clinically important problem. Obviously with this very lowestrogen dose, in the case of many females, the maturation of follicles,which could be detected with ultrasonic studies or hormonal studies,results [(6.) Lunell, N. O.; Carlström, K.; Zador, G.; Ovulationinhibition with a combined oral contraceptive containing 20 μg ofethinylestradiol and 250 μg of levonorgestrel; Acta. Obstet. Gynecol.Scand. Suppl. 88: 17-21 (1979); (7.) Mall-Haefeli, M.; Werner-Zodrow,I.; Huber, P. R.; Klinische Erfahrungen mit Mercilon und Marvelon unterbesonderer Berücksichtigung der Ovar-Funktion [Clinical Experience withMercilon and Marvelon under special consideration of the ovaryfunction]; Geburtsh. und Frauenheilk. [Obstetrics and Gynecology] 51,35-38, Georg Thieme Verlag, Stuttgart-New York (1991); (8.) Strobel, E.,Behandlung mit oralen Kontrazeptiva [Treatment with OralContraceptives]; Fortschr. Med. Vol. 110, No. 20 (1992); (9.) Letter toEditor, Contraception 45: 519-521 (1992); (10.) Teichmann, A. T.; Brill,K.; Can Dose Reduction of Ethinylestradiol in OCs Jeopardize OvarianSuppression and Cycle Control? Abstract Book, VIIIth World Congress onHuman Reproduction, Bali, Indonesia (1993)].

The hormone determinations performed showed that functional granulosacells that secrete 17β-estradiol are involved. Each intake error in thecase of females with clear ovarian activity, thus with follicularmaturations, can result in a quick increase of gonadotropin production.The requirements for an ovulation would thus be present. It is estimatedthat approximately one third of females take oral contraceptivesirregularly within one year of use (Gynpress, Volume 1, No. 3, 1990).The risk of a pregnancy is therefore high especially in the case ofintake errors with the 20 μg ethinylestradiol preparations.

The object of this invention is an improved single-phase combinationpreparation for a female of reproductive age, who is not yet inpremenopause, containing an estrogen and gestagen in each individualdosage unit, with the lowest possible estrogen content in eachindividual dosage unit, but also with a low total hormone content peradministration cycle.

It has now been found that a pronounced ovarian suppression withoutfrequent follicular maturations with low daily estrogen dosage, lowtotal estrogen as well as low total hormone amount per administrationcycle can be achieved by the use of a composition comprising an estrogenselected from

-   -   2.0 to 6.0 mg of 17β-estradiol and    -   0.015 to 0.020 mg of ethinylestradiol;        and a gestagen selected from    -   0.05 to 0.075 mg of gestodene,    -   0.075 to 0.125 mg of levonorgestrel,    -   0.06 to 0.15 mg of desogestrel,    -   0.06 to 0.15 mg of 3-ketodesogestrel,    -   0.1 to 0.31 to 3 mg of drospirenone,    -   0.1 to 0.21 to 2 mg of cyproterone acetate,    -   0.2 to 0.3 mg of norgestimate and    -   >0.35 to 0.75 mg of norethisterone.        for the production of a form of dosage for contraception for a        female of reproductive age, who has not yet reached        premenopause, by administration of the form of dosage for 23 or        24 days, beginning on day one of the menstrual cycle (first day        of menstrual bleeding), followed by 5 or 4 pill-free or sugar        pill days, during a total of 28 days in the administration        cycle.

The terms “premenopause” and “menopause” are used within the scope ofthis invention in the meaning of the conventional definition, see, forexample, “The Controversial Climacteric,” P. A. of Keep et al., Ed., MTPpress (1981), e.g., p. 9.

The daily hormone dose is kept to a very low level here, while the usual21-day intake is extended by two or three days. The remaining 5 or 4days of a cycle are preferably bridged over by placebos, to avoid intakeerrors, or by 5 or 4 intake-free days.

According to a preferred embodiment of this invention, this relates tothe use of a composition comprising an estrogen selected from

-   -   >2.0 to 6.0 mg of 17β-estradiol and    -   0.020 mg of ethinylestradiol;        and a gestagen selected from    -   >0.06 to 0.075 mg of gestodene,    -   >0.100 to 0.125 mg of levonorgestrel,    -   >0.10 to 0.15 mg of desogestrel,    -   >0.10 to 0.15 mg of 3-ketodesogestrel,    -   0.25 to 0.302.5 to 3.0 mg of drospirenone,    -   0.1 to 0.21 to 2 mg of cyproterone acetate,    -   0.2 to 0.3. mg of norgestimate and    -   0.50 to 0.75 mg of norethisterone        for the production of a form of dosage for contraception as        described above.

In addition, this invention relates to a combination product for oralcontraception, which comprises

a) 23 or 24 dosage units, each containing an estrogen selected from

-   -   >2.0 to 6.0 mg of 17β-estradiol and    -   0.020 mg of ethinylestradiol;        and a gestagen selected from    -   >0.06 to 0.075 mg of gestodene,    -   >0.100 to 0.125 mg of levonorgestrel,    -   >0.10 to 0.15 mg of desogestrel,    -   >0.10 to 0.15 mg of 3-ketodesogestrel,    -   0.25 to 0.302.5 to 3.0 mg of drospirenone,    -   0.1 to 0.21 to 2 mg of cyproterone acetate,    -   0.2 to 0.3 mg of norgestimate and    -   0.50 to 0.75 mg of norethisterone        and

b) 5 or 4 sugar pills or other indications to show that the dailyadministration of 23 or 24 dosage units is to be followed by 5 or 4pill-free or sugar pill days are to be followed.

Further embodiments according to the invention follow from the featuresof the subclaims.

An especially preferred combination preparation according to thisinvention comprises 23 dosage units, each containing 20 μg ofethinylestradiol and 75 μg of gestodene and 5 sugar pills or otherindications to show that no dosage unit or a sugar pill is administeredduring the last 5 days of the menstrual cycle.

The clinical study briefly described below was performed withethinylestradiol as estrogen and gestodene as representative of thesubstance class of the gestagens possible according to the invention.All possible combinations of ethinylestradiol or estradiol according tothe invention in the indicated dosages with one of the selectedgestagens in the indicated dosages as 23- or 24-day preparations exhibitthe advantages according to the invention.

The 23-day administration of 20 μg of ethinylestradiol in combinationwith 75 μg of gestodene results, in comparison to the 21-dayadministration, in a stronger ovarian suppression. In a double-placebo,randomized study on healthy females with normal ovarian function, groupsof 30 test subjects each received the combination preparation eitheronce daily over 21 or 23 days as well as placebos on 7 or 5 days (toassure the double-placebo nature of the study).

The treatment began after an ovulatory, untreated preliminary cycle onthe first day of the menstrual bleeding of the subsequent cycle andextended altogether over three treatment cycles. The study was concludedwith an untreated follow-up cycle.

The ovarian suppression was measured based on the level of theendogenous 17β-estradiol level and the size of follicular structures.The results show that the 17β-estradiol levels with 23-day intake of thetest preparation were significantly lower (p<0.05) in comparison to the21-day administration (FIG. 1).

In accordance with this finding, the number of females with follicularmaturations was also clearly higher in the 21-time administrationrelative to the 23-time administration (FIG. 2).

The intake interval extended only by two days surprisingly produces asignificantly greater ovarian suppression with unchangingly low dailydoses. The combination preparation according to the invention thusachieves the effectiveness previously known for preparations with adaily content of 30 μg of ethinylestradiol, although the dailyethinylestradiol dose is 33% lower and also the total dose per cycle is27% lower.

The advantages of a combination preparation for oral contraception to beadministered over 23 days relative to the usual 21-day preparations withless than 30 μg of ethinylestradiol can be characterized as follows:

1. A significantly lower frequency of follicular developments in theuser (maximum of 13% in females who received the 23-day preparationrelative to a maximum of 40% among those who received the 21-daypreparation). This means a greater contraceptive reliability of the23-day preparation, especially in the case of previous intake errors.The danger of “breakthrough ovulations” is smaller.

2. The occurrence of large follicles of more than a 30 mm diameter isextremely rare. The development of ovarian cysts is improbable with the23-day preparation in comparison to the 21-day preparation.

3. The recruitment of dominant follicles is suppressed in the shortenedintake-free pause.

4. The endogenous 17β-estradiol levels are suppressed easilycontrollably in the case of the majority of the users of the 23-daypreparation. Clinical symptoms such as breast tenseness, premenstrualsyndrome and menstrual disorders, which can be attributed to increasedand greatly fluctuating estrogen levels, are observed with the 23-daypreparation with clearly lower frequency.

In summary, an intake, extended by two (or three) days, of preparationscontaining 20 μg of ethinylestradiol in each daily dosage unit canproduce the above-mentioned advantages, without the daily dose having tobe raised to the previously largely used level of 30 μg ofethinylestradiol.

The formulation of an estrogen and gestagen for the use according to theinvention or for a combination preparation according to the inventiontakes place completely analogously as it is already known for usual oralcontraceptives with 21-day intake period of the active ingredients, suchas, for example, Femovan® (ethinylestradiol/gestodene) or Microgynon®(ethinylestradiol/levonorgestrel).

A pack containing a combination preparation according to the inventionis also designed analogously to packs for already known oralcontraceptives on the market with the variation that instead of theusual 21 dosage units containing the active components, now 23 or 24such dosage units and 5 or 4 sugar pills are present or else containother suitable indications that 5 or 4 days are to be bridged over untilcontinuation of the intake of active ingredient-containing dosage units.

Moreover, reference is made to the statements made in EP-A 0 253 607,especially also to the statements there for determination of equivalentamounts of ethinylestradiol and 17β-estradiol, on the one hand, andvarious gestagens, such as levonorgestrel, desogestrel,3-ketodesogestrel and gestodene, on the other hand.

For further details for the determination of dose equivalents of variousgestagenic active ingredients, reference is made to “Probleme derDosisfindung: Sexualhormone” [Problems of Dose-Finding: Sex Hormones];F. Neumann et al. in “Arzneimittelforschung” (Pharmaceutical AgentResearch) 27, 2a, 296-318 (1977), as well as to “Aktuelle Entwicklungenin der hormonalen Kontrazeption” [Current Developments in HormonalContraception]; H. Kuhl in Gynäkologe” [Gynecologist) 25: 231-240(1992).

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1: Area with the 17β-estradiol level in groups of 30 females, whoare treated with an oral contraceptive (75 μg of gestodene+20 μg ofethinylestradiol) in 21- or 23-day administration interval over threecycles.

FIG. 2: Number of females in %, who showed follicular developments (>13mm diameter) with 21- or 23-day treatment with an oral contraceptive (75μg of gestodene+20 μg of ethinylestradiol).

We claim:
 1. A combination product for oral contraception, comprising(a) 23 or 24 dosage units, each containing an estrogen selectedfrom >2.0 to 6.0 mg of 17β-estradiol and 0.020 mg of ethinylestradiol;and a gestagen selected from 0.25 to 0.30 mg of drospirenone and 0.1 to0.2 mg of cyproterone acetate, and b) 5 or 4, respectively, activeingredient-free placebo pills or other indications to show that thedaily administration of the 23 or 24 dosage units respectively, is to befollowed by 5 or 4, respectively pill-free or placebo pill days.
 2. Acombination preparation for oral contraception according to claim 1,wherein the estrogen is ethinylestradiol.
 3. A combination preparationof claim 2, wherein the gestagen is cyproterone acetate.
 4. Acombination preparation of claim 2, wherein the gestagen isdrospirenone.
 5. A combination preparation according to claim 1, whereinthe estrogen is present in a dose of 20 μg of ethinylestradiol or anequivalent dose of 17β-estradiol and the gestagen is present in a doseequivalent to 75 μg of gestadene.
 6. A combination preparation accordingto claim 1, which comprises 23 dosage units and 5 placebo pills or otherindications to show that no dosage unit or a placebo pill isadministered during the last 5 days of the menstrual cycle.
 7. Acombination preparation according to claim 1, which comprises 23 dosageunits, each containing 20 μg of ethinylestradiol and a dose ofcyproterone acetate or drospirenone equivalent to 75 μg of gestodene and5 placebo pills or other indications to show that no dosage unit or aplacebo pill is administered during the last 5 days of the menstrualcycle.
 8. A combination preparation of claim 1, wherein the estrogen is17β-estradiol.
 9. A combination preparation of claim 8, wherein thegestagen is cyproterone acetate.
 10. A combination preparation of claim8, wherein the gestagen is drospirenone.
 11. A method of inducingcontraception in a female of reproductive age who has not yet reachedpremenopause, comprising administering to said female a monophasiccomposition that effectively lessens premenstrual syndrome, comprising0.015 to 0.020 mg of ethynylestradiol and 1-3 mg of drospirenone,wherein the composition is administered for 23 or 24 days, beginning onday one of the menstrual cycle, followed by 5 or 4 pill-free or sugarpill days, during a total of 28 days in the administration cycle.
 12. Amethod of claim 11 wherein the amount of ethynylestradiol is 0.020 mgand the amount of drospirenone is 3 mg.
 13. A method of claim 12 whereinthe composition is administered for 24 days, beginning on day one of themenstrual cycle, followed by 4 pill-free or sugar pill days, during atotal of 28 days in the administration cycle.
 14. A method of inducingcontraception in a female of reproductive age who has not yet reachedpremenopause, comprising administering to said female a monophasiccomposition that effectively lessens breast tenderness, comprising 0.015to 0.020 mg of ethynylestradiol and 1-3 mg of drospirenone, wherein thecomposition effectively lessens breast tenderness, and is administeredfor 23 or 24 days, beginning on day one of the menstrual cycle, followedby 5 or 4 pill-free or sugar pill days, during a total of 28 days in theadministration cycle.
 15. A method of claim 14 wherein the amount ofethynylestradiol is 0.020 mg and the amount of drospirenone is 3 mg. 16.A method of claim 15 wherein the composition is administered for 24days, beginning on day one of the menstrual cycle, followed by 4pill-free or sugar pill days, during a total of 28 days in theadministration cycle.
 17. A method of claim 11 wherein the compositioneffectively lessens breast tenderness.
 18. A method of claim 17 whereinthe amount of ethynylestradiol is 0.020 mg and the amount ofdrospirenone is 3 mg.
 19. A method of claim 18 wherein the compositionis administered for 24 days, beginning on day one of the menstrualcycle, followed by 4 pill-free or sugar pill days, during a total of 28days in the administration cycle.
 20. A method of inducing contraceptionin a female of reproductive age suffering from premenstrual syndrome whohas not yet reached premenopause, comprising administering to saidfemale a monophasic composition comprising 0.015 to 0.020 mg ofethynylestradiol and 1-3 mg of drospirenone, wherein the composition isadministered for 23 or 24 days, beginning on day one of the menstrualcycle, followed by 5 or 4 pill-free or sugar pill days, during a totalof 28 days in the administration cycle.
 21. A method of claim 20 whereinthe amount of ethynylestradiol is 0.020 mg and the amount ofdrospirenone is 3 mg.
 22. A method of claim 21 wherein the compositionis administered for 24 days, beginning on day one of the menstrualcycle, followed by 4 pill-free or sugar pill days, during a total of 28days in the administration cycle.
 23. A method of inducing contraceptionin a female of reproductive age suffering from breast tenderness who hasnot yet reached premenopause, comprising administering to said female amonophasic composition comprising 0.015 to 0.020 mg of ethynylestradioland 1-3 mg of drospirenone, wherein the composition is administered for23 or 24 days, beginning on day one of the menstrual cycle, followed by5 or 4 pill-free or sugar pill days, during a total of 28 days in theadministration cycle.
 24. A method of claim 23 wherein the amount ofethynylestradiol is 0.020 mg and the amount of drospirenone is 3 mg. 25.A method of claim 24 wherein the composition is administered for 24days, beginning on day one of the menstrual cycle, followed by 4pill-free or sugar pill days, during a total of 28 days in theadministration cycle.
 26. A method of claim 20 wherein the female ofreproductive age suffers from breast tenderness.
 27. A method of claim26 wherein the amount of ethynylestradiol is 0.020 mg and the amount ofdrospirenone is 3 mg.
 28. A method of claim 27 wherein the compositionis administered for 24 days, beginning on day one of the menstrualcycle, followed by 4 pill-free or sugar pill days, during a total of 28days in the administration cycle.